This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neuropilin is an essential bi-functional mammalian cell surface receptor functioning in both angiogenesis and axon guidance. Neuropilin is of particular medical importance since in addition to its normal roles, it also is required for VEGF dependent tumor angiogenesis, facilitating neo-vascularization and growth of solid tumors. During both normal and tumor-angiogenesis, neuropilin binds members of the VEGF family of ligands and functions as a co-receptor for the VEGF-R receptor tyrosine kinases. During neural development, neuropilin binds members of the semaphorin III family of ligands and functions as a co-receptor for members of the plexin family of receptors. We seek to understand neuropilin ligand binding, specificity, and receptor activation. Additionally, we seek to inform ongoing studies to define novel anti-angiogenesis targets. Fundamentally, our goal will be to answer the following questions: How does neuropilin activate and regulate VEGF dependent angiogenesis and semaphorin dependent axon guidance? These studies will define common features of ligand binding as well as unique features that determine specificity between different protein homologues and isoforms. Further studies will characterize the mechanism(s) by which ligand binding to neuropilin couples to activation of intracellular signaling.